US Researchers discover how a molecular switch regulates fat and cholesterol metabolism pathway

Findings may contribute to understanding and
treatment of metabolic syndrome conditions that can lead to heart
disease

Researchers at Harvard Medical School and Massachusetts General Hospital
have identified how a molecular switch regulates fat and cholesterol
production, a step that may help advance treatments for metabolic syndrome,
the constellation of diseases that includes high cholesterol, obesity,
type II diabetes, and high blood pressure. The study is now published
in the online version of the scientific journal Nature and will appear
in the August 10th print edition.

"We have identified a key protein that acts together with
a family of molecular switches to turn on cholesterol and fat (or
lipid) production,"
said
principal investigator Anders Näär, PhD, assistant professor
of cell biology at Harvard Medical School and the Massachusetts General
Hospital Cancer Center.

" The identification of this protein
interaction and the nature of the molecular interface may one day
allow us to pursue
a more comprehensive approach to the treatment of metabolic syndrome."

High levels of cholesterol and lipids are linked to a number of interrelated
medical conditions and diseases, including obesity, type II diabetes,
fatty liver, and high blood pressure. This set of conditions and diseases,
known as metabolic syndrome, are afflicting a rapidly increasing portion
of society and serve as a major risk factor for heart disease, the
leading cause of death in the developed world..

Treatments for diseases associated with metabolic syndrome have focused
primarily on individual elements, such as high LDL-cholesterol (targeted
by the cholesterol-lowering statin drugs). However, more effective
ways to treat all of the components of metabolic syndrome are needed.
One attractive approach might be to target the genetic switches that
promote cholesterol and lipid synthesis, but it would require a detailed
understanding of the regulatory mechanisms before drug targets can
be identified.

After eating a meal, a family of proteins act as switches to turn
on cholesterol and fat (or lipid) production. This family of proteins
is known as SREBPs, or sterol regulatory element binding proteins.
Between meals, the production of cholesterol and lipids should be turned
off, however, excess intake of foods, coupled with lack of exercise,
appear to disturb the normal checks and balances that control SREBPs,
resulting in overproduction of cholesterol and lipids.

In the Nature paper, the HMS and MGH Cancer Center team has shown
that a protein called ARC105, which binds to SREBPs, is essential in
controlling the activity of the SREBP family of proteins.

" ARC105
represents a lynchpin for SREBPs control of cholesterol and lipid
biosynthesis genes, which may provide a potential molecular Achilles
heel that could
be targeted by drugs" said Dr. Näär.

The researchers initially found that after removing ARC105 from human
cells by a process called RNAi, SREBPs were no longer able to activate
cholesterol and lipid biosynthesis genes. To validate these findings
in a physiological setting, the researchers turned to the microscopic
worm C. elegans, a favorite model organism among those studying evolutionarily
conserved biological processes because of its rapid generation time
and relative simplicity of genetics, and which had previously been
used to study mechanisms of fat regulation.

Through a collaborative effort with the worm genetics group of Anne
Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center,
the team demonstrated that the C. elegans homologues of SREBP and ARC105,
known as SBP-1 and MDT-15, respectively, are necessary for production
and storage of fat. The worms had regular fat production when SBP-1
and MDT-15 functioned normally, but when researchers used RNAi to knock
out function of either SBP-1 or MDT-15, the worms lost their ability
to properly store fat, lay eggs, and move normally.

" The striking effects of the RNAi knock downs in C. elegans
suggest that the ARC105/SREBP pathway may play a key role in lipid
production
in humans,"
said Laurie Tompkins, PhD, of the National Institute
of General Medical Sciences, which partially supported the research.

" This
work highlights the value of model organisms in helping us understand
cellular processes that impact human health."

The research team also showed that removal of ARC105 in human cells
by RNAi also negatively affects the same key SREBP target gene as identified
in C. elegans. This suggests that the molecular switch is evolutionarily
conserved (and therefore likely physiologically important).

Exhaustive biochemical detective work performed by the Näär
group together with the group of Gerhard Wagner, PhD, HMS professor
in the Department of Biological Chemistry and Molecular Pharmacology,
identified exactly how SREBP and ARC105 interact. They found a flexible
tail on the SREBP molecule that fits into a specific groove on a region
of ARC105 called KIX.

The researchers analyzed the amino acid sequence of the ARC105 protein,
testing many different sections using NMR spectroscopy to eventually
find the KIX area-just one tenth the area of the larger ARC105 protein-that
specifically binds to SREBP. This specific interaction between SREBP
and ARC105 might be a target for small molecule drugs, according to
Dr. Wagner.

" While RNAi completely knocks out a protein including its
other functions, perhaps not related to fat metabolism, a small molecule
is a more subtle tool that could eliminate one protein-to-protein interaction,"
said
Dr. Wagner.

Finding a molecule that attaches to and inhibits the
flexible tail of SREBP is unlikely, but a search for inhibitors
to fit the grooved
KIX site looks much more promising.

The team is already initiating high-throughput screening at Harvard
Medical School's Institute of Chemistry and Cell Biology to identify
small molecule inhibitors of the KIX site.

Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH conducts
the largest hospital-based research program in the United States, with
an annual research budget of nearly $500 million and major research
centers in AIDS, cardiovascular research, cancer, computational and
integrative biology, cutaneous biology, human genetics, medical imaging,
neurodegenerative disorders, regenerative medicine, transplantation
biology and photomedicine. MGH and Brigham and Women's Hospital are
founding members of Partners HealthCare HealthCare System, a Boston-based
integrated health care delivery system.

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on 2 August 2006 and may have been edited for
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here.

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